Overall Summary Tobacco smoking is the leading preventable cause of cancer death. However, healthcare systems have not realized their potential to reduce smoking prevalence; far too few patients who smoke are offered and use smoking treatments and such treatments are insufficiently effective. This Program Project addresses these key obstacles by developing an especially effective comprehensive chronic care smoking treatment to reduce smoking prevalence in healthcare via 4 individual projects and 3 cores. This Program Project will balance internal and external validity via powerful, innovative research methods such as the Multiphase Optimization Strategy (MOST) while also using real-world primary care clinics, patients, and staff, and using the RE-AIM framework to enhance its public health impact. Using a factorial design, the Cessation Screening Project will evaluate four experimental factors in 608 smokers willing to quit to determine, for the first time, which intervention strategies (Preparation Medication, Extended Medication, and Counseling Modality) combine to produce especially effective Optimized Varenicline and Combination Nicotine Replacement Therapy (C-NRT) Treatment Packages based on cost and 1-year abstinence. The Health System Reach Interventions Project will, for the first time, use a factorial experiment to evaluate three interventions intended to increase the use of cessation treatments (i.e., reach) over 2 years in 1664 smokers initially unwilling to quit: 1) Monetary Incentives to Use Smoking Treatment, 2) Electronic Health Record (EHR) Based Automated Tailored Outreach, and 3) Care Management. An Optimized Reach Intervention Package will be developed that produces especially high rates of varenicline and C-NRT cessation treatment use by smokers initially unwilling to quit. The Optimized Care Project will comprise two randomized controlled trials (RCTs) that evaluate the Optimized Cessation and Reach Intervention Packages developed in the Cessation and Reach Projects. One RCT will compare Optimized Cessation Treatment versus Standard Care (physician & quitline referral) on 1-year abstinence in 600 smokers willing to quit. The second RCT will compare combined Optimized Reach and Cessation Interventions versus Standard Care on cessation treatment use and 1-year abstinence in 900 smokers initially unwilling to quit. The Implementation Project will assess the reach, implementation (fidelity, adaptation, relation with effectiveness), patient representativeness, and maintenance of interventions in the other 3 projects using EHR, survey, qualitative, and observational data at patient, staff, clinic, and system levels. This Program Project will be supported by Administration & Logistics, Data Analysis, and Optimization Cores and by shared resources: collaborating healthcare systems and recruitment via an enhanced EHR. This Program Project will develop a chronic care smoking treatment for healthcare that includes optimized reach and cessation interventions that can be readily implemented and disseminated and that markedly increase the use and effectiveness of cessation treatment, ultimately reducing smoking prevalence and cancer deaths.